The Insulin Resistance Syndrome (IRS) augments risk for cardiovascular disease in patients both with and without diabetes. The development of the IRS is integrally coupled to increased abdominal fat and waist/hip ratio. Our data show that an abnormal NMR lipoprotein subclass profile is associated with high waist/hip and confers increased vascular disease risk in Type 1 diabetes. The dyslipidemic pattern is identical to that observed in normoglycemic IRS and Type 2 Diabetes, and can be reserved by insulin-sensitizing thiazolidinediones. The link between increased abdominal fat and biochemical risk factors in IRS is unknown. Adipocytes secrete a large number of paracrine and endocrine factors that influence adipocyte size and function as well as whole-body physiology. The overall goal of Project 5 is to assess for the first time the effects of secreted adipocyte proteins on the biochemical risk profile and cardiovascular disease events in diabetes and IRS. The studies will involve unique national cohorts of Type 1 (DCCT/EDIC) and 2 (VA Cooperative Trial) diabetic patients, combined with in vitro studies, in order to test specific hypotheses from both epidemiological and mechanistic perspectives. In Specific Aim 1 we will measure circulating levels of novel adipocyte-derived proteins including adiponectin, acylation stimulating protein, CETP, PLTP, PAI-1, angiotensinogen, and leptin, and assess their relationship with cardiovascular risk factors and clinical events in both diabetes cohorts. In Specific Aim 2, we will determine the effects of thiazolidinedione treatment in Type 2 Diabetes on secreted adipocyte proteins, the biochemical risk profile, and cardiovascular events. In Specific Aim 3, we will study cultured adipocytes from insulin sensitive, IRS, and Type 2 diabetics, and assess the secretion rate of adipocyte proteins in vitro to directly assess whether changes in circulating levels are correlated with in vitro secretion rates. We will also study regulation of protein secretion by substrates, autocrine/paracrine factors, and thiazolidinediones. In Specific Aim 4, we will examine whether specific gene polymorphisms influence secretion of adipocyte proteins and cardiovascular disease risk in diabetes. These studies will determine whether secreted adipocyte proteins are responsible for multiple traits in the IRS cluster, and the role of the IRS in mediating increased risk for cardiovascular disease in diabetes.